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Background. The duration of protection in children and adults resulting from hepatitis B vaccination is unknown. In 1981, we
immunized a cohort of 1578 Alaska Native adults and children from 15 Alaska communities aged ≥6 months using 3 doses of plasma-
derived hepatitis B vaccine.
Methods. Persons were tested for antibody to hepatitis B surface antigen (anti-HBs) levels 30 years after receiving the primary
series. Those with levels <10 mIU/mL received 1 booster dose of recombinant hepatitis B vaccine 2–4 weeks later and were then eval-
uated on the basis of anti-HBs measurements 30 days after the booster.
Universal vaccination with hepatitis B vaccine has been very ef- [12, 14–16]. After 22 years, 60% had a protective level of anti-
fective at preventing infection with the hepatitis B virus (HBV) body to hepatitis B surface antigen (anti-HBs; ≥10 mIU/mL),
and at reducing the development of chronic infection in young and overall 93% seemed to be protected (had antibody and/or
children from perinatal or early childhood exposures to HBV responded to booster dose). In addition, no new acute or chron-
[1–6]. However, the duration of protection after vaccination of ic HBV infections were found at this time [12].
infants (immunized from birth), older children and adults (with In this study, conducted 30 years after primary vaccination
either plasma-derived or recombinant vaccine) is not well un- series, we recruited a subset of the original cohort with the fol-
derstood [7–11]. We previously demonstrated protection out lowing goals: (1) to determine the proportion of persons with
to 22 years among persons vaccinated as children or adults anti-HBs levels ≥10 mIU/mL, (2) to evaluate the immune re-
[12–14]. sponse to a booster dose of hepatitis B vaccine among those
After US licensure of the HBV vaccine in 1981, we immu- with anti-HBs <10 mIU/mL, and (3) to compare characteristics
nized a cohort of 1578 Alaska Native adults and children aged of persons with or without protective antibody levels.
≥6 months with 3 doses of the plasma-derived hepatitis B vac-
cine [15]. Persons <20 years of age received the 10-µg dose, METHODS
and adults (aged ≥20 years) received the 20-µg dose. We fol- Study Design
lowed this cohort yearly with HBV serologic testing for the first This study was performed in a long-term prospective cohort.
11 years and then 15 and 22 years after their first dose of vaccine
Participants
We enrolled participants from 12 of the original 15 communi-
Received 8 September 2015; accepted 27 October 2015.
Correspondence: M. G. Bruce, Arctic Investigations Program, Centers for Disease Control and
ties in the 1981 immunogenicity study with a documented re-
Prevention, 4055 Tudor Centre Dr, Anchorage, AK 99507 (zwa8@cdc.gov). sponse to the primary plasma-derived hepatitis B vaccine series.
The Journal of Infectious Diseases® Persons in the 3 communities who did not participate did not
Published by Oxford University Press for the Infectious Diseases Society of America 2016. This
work is written by (a) US Government employee(s) and is in the public domain in the US.
differ from all others in terms of age, sex, and initial antibody
DOI: 10.1093/infdis/jiv748 level after the primary series. Persons from these 12 communities
2 • JID • Bruce et al
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Figure 1. Participant flow chart in a 30-year follow-up study of 1578 persons receiving 3 doses of plasma-derived hepatitis B virus (HBV) vaccine in Alaska in 1981.
Abbreviation: anti-HBs, antibody to hepatitis B surface antigen.
Anti-HBs Levels 85 (66%) had anti-HBs levels ≥10 mIU/mL, and the GMC of anti-
Overall, among the 435 study participants, 219 (50%) had anti- HBs was 24.6 mIU/mL. Among the 63 study participants in group
HBs levels ≥10 mIU/mL; the GMC of anti-HBs was 13.8 mIU/ 3, only 9 (14%) had anti-HBs levels ≥10 mIU/mL 8 years after
mL. GMCs by group during the 30-year period (Figure 2) high- their booster dose, and the GMC of anti-HBs was 3.6 mIU/mL.
light the fact that group 3 has had consistently lower GMCs than Analysis of data from group 1 by multivariate logistic regres-
group 1, and group 2 consistently higher GMCs. Antibody levels sion demonstrated that initial anti-HBs level and age at primary
at 30 years by sex, age, and anti-HBs level at study enrollment are vaccination were associated with anti-HBs levels ≥10 mIU/mL at
shown for group 1 (Table 1). Among the 243 group 1 participants, 30 years. Persons aged 5–19 years at the time of primary vacci-
125 (51%) had anti-HBs levels ≥10 mIU/mL, and the GMC of nation (aged 35–49 years at 30-year follow-up) had higher GMCs
anti-HBs was 14.4 mIU/mL. Among the 129 group 2 participants, and a higher proportion of protective antibodies than study
Sex
Female 117 14.1 52 (61) .83 . . .
Male 126 14.7 51 (64)
Age at 30-y follow-up (age at primary vaccination), y
<35 (<5) 59 6.8 32 (19) <.001 .002
35 to <40 (5 to <10) 49 24.9 61 (30)
40 to <50 (10 to <20) 90 22.8 64 (58)
≥50 (≥20) 45 8.5 40 (18)
Anti-HBs level after primary series, mIU/mL
10 to <100 20 3.4 20 (4) <.001 <.001
100 to <1000 95 5.8 34 (32)
1000 to <5000 78 15.0 58 (45)
≥5000 50 136.9 88 (44)
BMI, kg/m2
<25 68 13.1 53 (36) .98 . . .
25 to <30 69 17.6 52 (36)
≥30 101 14.1 51 (52)
Ever smoked tobacco
Yes 168 14.1 51 (85) .48 . . .
No 72 16.6 56 (40)
Ever chewed tobacco
Yes 147 14.3 52 (76) .81 . . .
No 90 16.4 53 (48)
History of cancer
Yes 10 39.7 60 (6) .63 . . .
No 224 14.7 52 (117)
Self-reported HBV carrier in household
Yes 7 9.0 57 (4) >.99 . . .
No 178 15.3 52 (93)
Abbreviations: Anti-HBs, antibody to hepatitis B surface antigen; BMI, body mass index; GMC, geometric mean concentration; HBV, hepatitis B virus.
a
No persons had received a transplant, 3 had received immune-modulating medications, 6 had diabetes, 102 currently chewed tobacco, and 93 currently smoked.
4 • JID • Bruce et al
responded with anti-HBs levels ≥10 mIU/mL; the GMC was mIU/mL). Among the remaining 118 persons with anti-HBs
150.4 mIU/mL (Table 2). levels <10 mIU/mL, 75 of 85 available participants (88%) who
In the multivariate model, we determined that response to a received a booster dose responded with anti-HBs levels ≥10
booster dose was associated with the prebooster anti-HBs level; mIU/mL. Applying the 88% response rate to booster dose to
participants with preboost anti-HBs levels of 2–9.9 mIU/mL the larger group of 118 persons, 94% of primary responders
had a higher probability of achieving a response to booster had evidence of protective antibodies (anti-HBs levels ≥10
dose than those with anti-HBs levels <2 mIU/mL (P = .01; mIU/mL) or humoral immune memory defined by response
Table 2). No association was found between the proportion of to a booster dose. No new breakthrough infections were seen;
persons with anti-HBs levels ≥10 mIU/mL after the booster however, 2 persons who had previously been identified as pos-
dose and age at primary vaccination, anti-HBs level after pri- itive for antibody to hepatitis B core antigen remained so at 30
mary series, body mass index, smoking, or use of chewing to- years; HBV DNA was not detected.
bacco. In group 2, among the 36 persons tested 30 days after
DISCUSSION
the booster dose, 33 (92%) responded with anti-HBs levels
≥10 mIU/mL; the GMC was 419.8 mIU/mL. This study, which follows Alaska Native persons who had re-
Among the 243 group 1 participants, 125 (51%; 95% confi- ceived plasma-derived hepatitis B vaccine (at >6 months of
dence interval, 47%–55%) had evidence of long-term protection age) and who responded to the primary vaccine series at that
from hepatitis B vaccination (defined by anti-HBs levels ≥10 time, is the longest cohort study on long-term protection after
Sex
Female 38 266.2 87 (33) .75 . . .
Male 47 95.1 89 (42)
Age at 30-y follow-up (age at primary vaccination), y
<35 (<5) 30 98.2 83 (25) .77 . . .
35 to <40 (5 to <10) 17 134.2 94 (16)
40 to <50 (10 to <20) 19 275.7 89 (17)
≥50 (≥20) 19 179.4 89 (17)
Anti-HBs level after primary series, mIU/mL
10 to <100 9 33.7 89 (8) .08 . . .
100 to <1000 46 78.9 83 (38)
1000 to <5000 24 587.7 100 (24)
≥5000 6 876.3 83 (5)
BMI, kg/m2
<25 23 120.7 87 (20) .84 . . .
25 to <30 23 185.6 87 (20)
≥30 36 132.2 89 (32)
Ever smoked tobacco
Yes 61 128.4 87 (53) .72 . . .
No 22 218.9 91 (20)
Currently smokes tobacco
Yes 34 129.5 88 (30) >.99 . . .
No 49 162.1 88 (43)
Ever chewed tobacco
Yes 50 167.8 90 (45) .49 . . .
No 31 117.0 84 (26)
Currently chews tobacco
Yes 39 153.4 87 (34) >.99 . . .
No 46 148.3 89 (41)
Preboost anti-HBs level, mIU/mL
<2 39 40.1 82 (32) .04 .04
2–4 30 222.0 90 (27)
5–9.9 16 1837.4 100 (16)
Abbreviations: Anti-HBs, antibody to hepatitis B surface antigen; BMI, body mass index; GMC, geometric mean concentration.
6 • JID • Bruce et al
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